World-wide rates of obesity have reached epidemic proportions. In the United States alone 30% of the population is overweight and 30% is obese, contributing to an excess mortality of 300,000 deaths a year. Significant consequences of obesity include Type II diabetes and non-alcoholic fatty liver disease. Rates of Type II diabetes are rising in adults and worryingly, Type II is now also seen in adolescent patients. Despite the morbidity and mortality of obesity, few useful therapeutic agents have emerged and many current therapies used to treat diabetes induce additional weight gain. Fibroblast growth-fact 21 (FGF21) when administered pharmacologically to mice, has multiple beneficial effects including: improved glucose tolerance, activation of brown adipose tissue, browning of white adipose tissue, weight loss and anti-fibrotic and anti-inflammatory effects in the liver. Recent data suggest that beneficial effects are also seen in humans and thus FGF21 is considered a promising drug target. We found that in rodents FGF21 plays a role in browning of white adipose tissue in response to cold which is associated with beneficial metabolic consequences. Furthermore treatment with FGF21 mimics many of the effects of cold exposure. At least some of these effects are mediated by direct action through the central nervous system (CNS). We also found that FGF21 has anti- fibrotic and anti-inflammatory effects in the liver. However there are several significant uncertainties regarding it's mechanisms of action. In this proposal we will use an integrative physiologic approach to elucidate the effects of FGF21 on white adipose tissue, brown adipose tissue and liver. Many of the beneficial metabolic effects of FGF21 occur in an intact animal and cannot be reproduced in isolated tissue culture models. We believe that FGF21 integrates signals from the liver, brain and fat, and in the process of communicating between these 3 tissues, acts as a master regulator of whole body metabolism. We are particularly focused on distinguishing between effects mediated by the brain. We will focus on CNS mediated effects on the peripheral targets BAT, WAT & liver. We will also examine the differential effects of several potential downstream mediators. These include the fat derived hormone adiponectin and the mitochondrial-associated uncoupling protein 1 (UCP-1), an important mediator of increased energy expenditure, that can be activated through multiple pathways. We predict that FGF21 effects, such as weight loss and improved glucose homeostasis, depend on the ability of FGF21 to act in the CNS and activate browning through UCP-1. Other effects may reflect cell autonomous action on WAT, which may be mediated by adiponectin. Anti-inflammatory and anti- fibrotic effects on the liver will likely reflect direct ation on this tissue. We hope that with this physiologic approach we will be able to distinguish the integrative physiologic actions of FGF21 and uncover additional targetable systems for the therapy of metabolic disorders.